Search Results (14)

Malignant pleural mesothelioma (MPM) still represents a complex diagnostic challenge for pathologists in routine practice. This diagnosis requires a multidisciplinary approach, and pathological evaluation is mandatory. The histopathological diagnosis is stepwise and should be based on morphological and immunohistochemical assessment, sometimes associated with molecular tests, and supported by clinical and radiological findings. A correct morphological approach aims to exclude pleural metastasis or benign mesothelial proliferations, which are the main differential diagnoses. While certain histological features are diagnostic of MPM, others are highly suggestive but not definitive. Immunohistochemistry plays a pivotal role, with a panel of both traditional and newer markers being used to assess mesothelial differentiation and to differentiate malignant from benign proliferations. In more challenging cases, molecular tests, such as fluorescent in situ hybridization (FISH) to detect CDKN2A deletion, can be helpful in distinguishing malignant from benign pleural lesions. This review summarizes the key morphological, immunohistochemical, and molecular features that should be considered when pleural biopsy samples are examined, with the aim of improving diagnostic accuracy in this complex area. Full article

Background: Several tumor-associated macrophages (TAMs) have shown promise as prognosticators in cancer. Our aim was to validate the importance of TAMs in malignant pleural mesothelioma (MPM) using a two-stage design. Methods: We explored The Cancer Genome Atlas (TCGA-MESO) to select immune-relevant macrophage genes in MPM, including M1/M2 markers, as a discovery cohort. This computational cohort was used to create a multiplex immunofluorescence panel. Moreover, a cohort of 68 samples of MPM in paraffin blocks was used to validate the macrophage phenotypes and the co-localization and spatial distribution of these immune cells within the TME and the stromal or tumor compartments. Results: The discovery cohort revealed six immune-relevant macrophage genes (CD68, CD86, CD163, CD206, ARG1, CD274), and complementary genes were differentially expressed by M1 and M2 phenotypes with distinct roles in the tumor microenvironment and were associated with the prognosis. In addition, immune-suppressed MPMs with increased enrichment of CD68, CD86, and CD163 genes and high densities of M2 macrophages expressing CD163 and CD206 proteins were associated with worse overall survival (OS). Interestingly, below-median distances from malignant cells to specific M2a and M2c macrophages were associated with worse OS, suggesting an M2 macrophage-driven suppressive component in these tumors. Conclusions: The interactions between TAMs in situ and, particularly, CD206⁺ macrophages are highly relevant to patient outcomes. High-resolution technology is important for identifying the roles of macrophage populations in tissue specimens and identifying potential therapeutic candidates in MPM. Full article

Background: Local anaesthetic thoracoscopy (LAT) can be a vital procedure for diagnosis of unexplained pleural effusions. Traditionally, poudrage for pleurodesis and insertion of a large bore drain necessitated admission. There has been a shift towards performing LAT as a day case procedure with indwelling pleural catheter (IPC) insertion. This was advocated during the COVID pandemic by the British Thoracic Society (BTS). To determine the feasibility of such pathways, continuous evaluations are required. Methods: All day case LAT procedures with IPC insertion, performed in theatre, were identified at two large district general hospitals (Northumbria HealthCare in the North East of England and Victoria Hospital, NHS Fife, in Scotland). Rapid pleurodesis with talc was not performed due to local staffing problems. All patients had their LAT in theatre under conscious sedation with a rigid scope. Demographics, clinical, radiological and histopathological characteristics and outcomes were collected. Results: 79 patients underwent day case LAT. The lung did not deflate, meaning biopsies were not enabled, in four of the patients. The mean age was 72 years (standard deviation 13). Fifty-five patients were male and twenty-four were female. The main diagnoses were lung cancers, mesotheliomas and fibrinous pleuritis with an overall diagnostic sensitivity of 93%. Other diagnoses were breast, tonsillar, unknown primary cancers and lymphomas. Seventy-three IPCs were simultaneously placed and, due to normal macroscopic appearances in two patients, two large bore drains were placed and removed within one hour of LAT termination. Sixty-six (88%) patients were discharged on the same day. Seven patients required admission: one for treatment of surgical emphysema, four because they lived alone, one for pain control and one for control of a cardiac arrythmia. Within 30 days, there were five IPC site infections with two resultant empyemas (9%), with no associated mortality. Two patients developed pneumonia requiring admission and one patient required admission for pain management. The median number of days for which the IPCs remained in situ was 78.5 days (IQR 95). The median length of stay (LoS) was 0 days (IQR 0). No patients required further interventions for pleural fluid management. Conclusions: Day case LAT with IPC insertion is feasible with this current set up, with a median stay of 0 days, and should be widely adopted. The health economics of preventing admission are considerable, as our previous analysis showed a median length of stay of 3.96 days, although we are not comparing matched cohorts. Full article

Malignant pleural mesothelioma is a rare cancer characterized by a very poor prognosis. Exposure to asbestos is the leading cause of malignant pleural mesothelioma. The preinvasive lesions, the mesothelial hyperplasia and its possible evolution are the focus of the majority of the studies aiming to identify the treatable phase of the disease. The role of BAP-1 and MTAP in the diagnosis of mesothelioma in situ and in the prognosis of malignant pleural mesothelioma is the main topic of recent studies. The management of preinvasive lesions in mesothelioma is still unclear and many aspects are the subject of debate. The diagnosis, the disease staging and the accurate, comprehensive assessment of patients are three key instants for an appropriate management of patients/the disease. Full article

The 2021 WHO Classification of Tumors of the Pleura has introduced significant changes in mesothelioma codification beyond the three current histological subtypes—epithelioid, sarcomatoid and biphasic. Major advances since the 2015 WHO classification include nuclear grading and the introduction of architectural patterns, cytological and stromal features for epithelioid diffuse mesothelioma. Mesothelioma in situ has been recognized as a diagnostic category. Demonstration of loss of BAP1 or MTAP by immunohistochemistry, or CDKN2A homozygous deletion by FISH, is valuable in establishing the diagnosis of epithelioid mesothelioma. Recent emerging data proved that grading and histological subtypes have prognostic implications and may be helpful to patient risk stratification and clinical management. Nevertheless, the latest mesothelioma classification increases the already non-negligible diagnostic pitfalls, especially concerning differential diagnosis of pre-invasive tumors. In this review, recent changes in histologic classification of mesothelioma and advances in molecular markers are presented and their relation to diagnostic challenges and prognostic implications is discussed. Full article

Malignant Pleural Mesothelioma (MPM) is a highly aggressive disease whose diagnosis could be challenging and confusing. It could occur with atypical presentations on every examined level. Here, we present three unconventional cases of the complex diagnostic process of MPM that we have experienced during routine practice: a patient with reactive mesothelial hyperplasia mimicking MPM, an unexpected presentation of MPM with persistent unilateral hydropneumothorax, a rare case of MPM in situ. Then, we review the relevant literature on each of these topics. Definitive biomarkers to confidently distinguish MPM from other pleural affections are still demanded. Patients presenting with persistent hydropneumothorax must always be investigated for MPM. MPM in situ is now a reality, and this raises questions about its management. Full article

Pleural effusions are a common respiratory condition with many etiologies. Nonmalignant etiologies explain most pleural effusions and despite being nonmalignant, they can be associated with poor survival; thus, it is important to understand their pathophysiology. Furthermore, diagnosing a benign pleural pathology always harbors the uncertainty of a false-negative diagnosis for physicians and pathologists, especially for the group of non-specific pleuritis. This review aims to present the role of the inflammation in the development of benign pleural effusions, with a special interest in their pathophysiology and their association with malignancy. Full article

Malignant mesothelioma is a tumour of the serosal membranes, related to asbestos exposure. Median latency is in the order of 40 years in various registries, but small numbers of cases with shorter latencies have long been reported and often dismissed as unrelated to asbestos exposure. However, emerging data regarding the significance of inherited mutations leading to a predisposition to mesothelioma suggest that the causative effect of asbestos may be associated with shorter latencies in a subset of patients. Here, we describe a male patient with germline mutations in RAD51 and p53 who developed peritoneal mesothelioma 8.5 years after well-documented asbestos exposure and discuss the current literature on the subject. Mesothelioma in situ is now a WHO-accepted diagnosis, but preliminary data reveal a potential lead time of 5 or more years to invasive disease, and this is also a factor which may affect the recording of latency (and potentially survival) in the future. Full article

Thanks to clinically newly introduced inhibitors of the mesenchymal–epithelial transition (MET) receptor tyrosine-kinase, MET-gene copy number gain/amplification (MET-GCNG/GA) and increased expression of the MET protein are considered very promising therapeutic targets in lung cancer and other malignancies. However, to which extent these MET alterations occur in malignant mesothelioma (MM) remains unclear. Thus, we investigated by well-established immunohistochemistry and fluorescence in situ hybridization methods, the frequency of these alterations in specimens from 155 consecutive MMs of different subtypes obtained from pleural or peritoneal biopsies and pleurectomies. Thirty-three benign reactive mesothelial proliferations (RMPs) were used as controls. MET-protein upregulation was observed in 35% of all MM-cases, though restricted to predominantly epithelioid MMs. We detected low-/intermediate-level MET-GCNG/GA in 22.2% of MET-overexpressing MMs (7.8% of whole MM-cohort) and no MET-GCNG/GA in the other 77.8%, suggesting other upregulating mechanisms. In contrast, 100% of RMPs exhibited no MET-upregulation or MET-GCNG/-GA. Neither MET exon 14 skipping mutations nor MET-fusions were detected as mechanisms of MET overexpression in MM using RNA next-generation sequencing. Finally, in two cohorts of 30 MM patients with or without MET overexpression (MET-positive/-negative) that were matched for several variables and received the same standard chemotherapy, the MET-positive cases showed a significantly lower response rate, but no significant difference in progression-free or overall survival. Our results imply that MET overexpression occurs in a substantial fraction of predominantly epithelioid MMs, but correlates poorly with MET-amplification status, and may impact the likelihood of response to mesothelioma standard chemotherapy. The predictive significance of MET-IHC and -FISH for possible MET-targeted therapy of MM remains to be elucidated. Full article

Well-differentiated papillary mesothelioma has been renamed well-differentiated papillary mesothelial tumour (WDPMT) in the current WHO classification because all mesotheliomas are now regarded as malignant. WDPMT is now defined as a non-invasive papillary mesothelial proliferation, with retained labelling for BAP1-desirable. The current WHO classification also includes mesothelioma in situ (MIS), which is defined as pre-invasive flat or papillary proliferation of mesothelial cells with a loss of BAP1 or MTAP. WDPMT has been variably defined in the past but was thought to occur more commonly in women and pursue a more indolent course than mesothelioma, but its progression to invasive disease has occasionally been reported. Here, we report a case of a 68-year-old woman with a history of asbestos exposure and an underlying diagnosis of Ehlers Danlos syndrome who was diagnosed with symptomatic WDPMT of the peritoneum that progressed to mesothelioma within two years. On retrospective analysis, the WDPMT showed a loss of BAP1. We suggest that a loss of BAP1 in WDPMT should be reported, since these lesions may show aggressive behaviour, and that they may best be regarded as similar to mesothelioma in situ. Full article

Virtually any malignancy can metastasize to the liver. Large solitary metastases are rare and can be difficult to distinguish from primary tumors. Malignant mesothelioma is often considered as a locally invasive cancer but tumor dissemination to extra-thoracic sites is possible, and the liver can be involved. Herein, we present a rare case of pleural mesothelioma with a solitary large liver metastasis diagnosed postmortem in a ninety-two-year-old man with 35 years of exposure to asbestos. Results of immunohistochemical staining of the pleural and liver tumor were similar, both positive for low-molecular weight keratins, calretinin, vimentin, and podoplanin, and negative for Claudin-4, TTF1, CEA, BerEP4, CK7, CK19, CK20, BAP1, Hep Par1, p40, and WT1. Fluorescent in-situ hybridization (FISH) for p16/CDKN2A was also performed and a homozygous deletion was detected in both tumors, supporting the diagnosis of mesothelioma. Reporting this case, we would like to point out that extra-thoracic dissemination from pleural mesothelioma, even if exceptional, can occur. In cases where differential diagnoses are challenging, the value of ancillary techniques and a practical approach to diagnostic work-up is of primary importance. Full article

Background—There are currently no effective therapies for diffuse malignant peritoneal mesothelioma (DMPM) patients with disease recurrence. In this study, we investigated the biology of DMPM by analyzing the EGFR family, Axl, and MET, in order to assess the presence of cross-talk between these receptors, suggesting the effectiveness of combined targeted treatments in DMPM. Method—We analyzed a series of 22 naïve epithelioid DMPM samples from a single institute, two of which showed higher-grade malignancy (“progressed”). EGFR, HER2, HER3, Axl, and MET activation and expression were investigated by biochemical analysis, real-time PCR immunofluorescence, immunohistochemistry, next-generation sequencing, miRNA, and mRNA in situ hybridization. Results—In most DMPMs, a strong EGFR activation was associated with HER2, HER3, Axl, and MET co-activation, mediated mainly by receptor heterodimerization and autocrine-paracrine loops induced by the expression of their cognate ligands. Axl expression was downregulated by miRNA34a. Mutations in MET Sema domain were exclusively found in two “progressed” DMPMs, and the combined Axl and MET inhibition reduced cellular motility in a DMPM cell line obtained from a “progressed” DMPM. Conclusion—The results indicate that the coordinated activity of multiple cross-talks between RTKs is directly involved in the biology of DMPM, suggesting the combined inhibition of PIK3 and mTOR as an effective strategy that may be easily implemented in clinical practice, and indicating that the combined inhibition of EGFR/HER2 and HER3 and of Axl and MET deserves further investigation. Full article

Inhalation of fibrous erionite particles has been linked to malignant mesothelioma. Accordingly, erionite is considered the most carcinogenic mineral. The reactivity and the nature of erionite biotoxicity has been the subject of intensive research. Despite very close chemical and structural relationships between erionite and offretite, the reactivity of offretite in lung fluids remains unknown. In this paper, the interaction of erionite and offretite surfaces with simulated lung fluids was investigated by means of in situ atomic force microscope (AFM). To simulate different environments in the lungs, artificial lysosomal fluid (ALF) and Gamble’s solution were used. In ALF (4.15 < pH < 4.31) the dissolution of erionite and offretite surfaces was detected, as well as an evident removal of particles (mainly attributed to impurities) from the crystal faces. Instead, the growth of a layer of a yet unknown phase on the surface of both zeolites was observed during the interaction with Gamble’s solution (7.4 < pH < 8.48). The thickness of this layer reached a few tens of nanometers and covered all the observed areas. The understanding of the observed processes is of paramount importance, since they could be potentially involved in the mechanisms triggering the toxicological effects of erionite fibres. Full article

Malignant pleural mesothelioma (MPM) is a deadly cancer that is caused by asbestos exposure and that has limited treatment options. The current standard of MPM diagnosis requires the testing of multiple immunohistochemical (IHC) markers on formalin-fixed paraffin-embedded tissue to differentiate MPM from other lung malignancies. To date, no single biomarker exists for definitive diagnosis of MPM due to the lack of specificity and sensitivity; therefore, there is ongoing research and development in order to identify alternative biomarkers for this purpose. In this study, we utilized primary MPM cell lines and tested the expression of clinically used biomarker panels, including CK8/18, Calretinin, CK 5/6, CD141, HBME-1, WT-1, D2-40, EMA, CEA, TAG72, BG8, CD15, TTF-1, BAP1, and Ber-Ep4. The genomic alteration of CDNK2A and BAP1 is common in MPM and has potential diagnostic value. Changes in CDKN2A and BAP1 genomic expression were confirmed in MPM samples in the current study using Fluorescence In situ Hybridization (FISH) analysis or copy number variation (CNV) analysis with digital droplet PCR (ddPCR). To determine whether MPM tissue and cell lines were comparable in terms of molecular alterations, IHC marker expression was analyzed in both sample types. The percentage of MPM biomarker levels showed variation between original tissue and matched cells established in culture. Genomic deletions of BAP1 and CDKN2A, however, showed consistent levels between the two. The data from this study suggest that genomic deletion analysis may provide more accurate biomarker options for MPM diagnosis. Full article